N-acyliminium ions generation

The reactions of sterically encumbered allenylsilanes of structure type (66) with N-acyliminium ions generated by the dtanium tetrachloride promot reacdon of ethoxypyirolidinone produced the nitrogen heterocycle (70), as depicted in Figure 13. In this reacdon it is likely the lactam product is generated by a pathway similar to that involved in the [3 -) 2] cyclopentene anneladon. Thus, a regiospecific electro-... 

Treatment of the solid-supported amino acetals (529) with catalytic PTSA, followed by addition of IH-benzotriazole, resulted in the 2-benzotriazole-substituted piperidines (530) as stable N-acyliminium ion precursors, according to Katritzky [392]. A number of different carbon nucleophiles were then added to the N-acyliminium ions, generated under acid catalysis by either boron trifluoride etherate or camphorsulfonic acid (Scheme 107). 

Acid-induced reactions of silicon-containing unsaturated compounds with JV-acyliminium intermediates have proven particularly useful. Allylsilanes lead to the corresponding allyl-substituted products.84-85 This reaction proceeds well even for -lactams (equation 49).85,86 The penicillin-derived 4-acetoxyazet-idinone (91) reacts with excess allylsilane in refluxing dichloroethane, catalyzed by TMSOTf, to produce as the sole product trans compound (92).86 N-Acyliminium ions generated from cyclic ureas87 and carbamates (93)88 likewise yield allylated products with virtually complete trans stereoselectivity (equation SO). Allylstannanes react under somewhat milder conditions than allylsilanes, requiring only a catalytic amount of BFjZEtjO at room temperature for a (J-lactam system (equation S1 ).89 This allylstannane procedure was applied to cyclic carbamate systems for the stereoselective synthesis of several isomers of statine.90-91 Thus, ethoxycarbamate (94) reacts with methallyltributylstannane in excellent yield and dia-stereoselectivity (equation 52).91... 

A schematic diagram of the cation flow method for generating N-acyliminium ion 2 is shown in Fig. 5. A solution of carbamate 1 is introduced into the anodic compartment of electrochemical microflow cell, where oxidation takes place on the surface of a carbon fiber electrode. A solution of trifluoromethanesulfonic acid (TfOH) was introduced in the cathodic compartment, where protons are reduced to generate dihydrogen on the surface of a platinum electrode. A-Acyliminium ion 2 thus generated can be analyzed by an in-line FT-IR analyzer to evaluate the concentration of the cation. The solution of the cation is then allowed to react with a nucleophile such as allyltrimethylsilane in the flow system to obtain the desired product 3. 

In addition to electron-deficient alkenes, under the catalysis of TiCLt, 1,2-allenylsi-lanes can react with aldehydes or N-acyliminium ion to afford five-membered vinylic silanes 71 and 72. Here the carbocations generated by a Lewis acid regiospecifically attack the C3 of the 1,2-allenylsilanes to produce a vinyl cation stabilized by hyper-... 

Scheme 17 Generation of N-acyliminium ions by anodic decarboxylation.

V-Acyliminium ions are even more reactive toward alkenyl and allylic silanes. N-Acyliminium ions are usually obtained from imides by partial reduction. The partially reduced /V-acylcarbinolamincs can then generate acyliminium ions. Intramolecular examples of such reactions have been observed. 

Formation of iV-acyliminium ion under mild and almost neutral conditions makes a marked contrast to conventional methods where N-acyliminium ions are generated under acidic conditions from... 

An N-acyliminium ion C42 is also readily generated from an a-stannyl amino compound 42 by electrochemical oxidation, whereas the corresponding silyl derivative is less effective in this respect (Scheme 15). ... 

Since the seminal paper of Speckamp and Hiemstra [390], N-acyliminium ion species emerged as being among the most versatile of intermediates in the creation of new carbon-carbon bonds. The broad spectrum of reactivity of N-acylimin-ium ions toward different carbon nucleophiles, as well as their ability to participate as both dienophiles and electron-deficient heterodienes in cycloaddition reactions, has made them attractive potential solid-phase intermediates, allowing the generation of chemical diversity starting from a common precursor. 

Aiming to prepare a library of derivatives of the medicinally relevant piperidine scaffold, Veerman [393] and co-workers exploited N-acyhminium ion chemistry, starting from a stable aminal precursor. Coupling of six different amino acetals onto sulfonylethoxycarbonyl-modified (SEC-modified) polystyrene resin afforded the potential precursors. However, attempts to transform these into the desired piperidine derivatives via one-pot generation of N-acyliminium ions and functionalization failed, essentially because direct attack of the nucleophile on the acid-mediated oxycarbenium ion took place at a similar rate to that of the intramolecular carbamate-nitrogen attack. 

Due to the fact that a,[3-unsaturated aldehydes are not compatible with the classical Pictet-Spengler reaction conditions, the generation of a highly reactive N-acyliminium ion, derived from an a,[3-unsaturated imine via its acylation, could represent a viable strategy to overcome the aforementioned issue. 

The following example illustrates how a cation pool of an N-acyliminium ion is generated and used for a subsequent reaction. Low-temperature electrolysis of pyrrolidine carbamate in BU4NBF4/CH2CI2 gives a solution of the corresponding N-acyliminium ion as a single species,as... 

The reaction of an N-acyliminium ion pool with an alkene or alkyne followed by trapping of the resulting carbocation by water leads to the formation of the corresponding carbohydroxylation product. Cationic sequential one-pot, three-component coupling reactions of an N-acyliminium ion can also be accomplished using an electron-rich olefin and a suitable nucleophile that traps the thus-generated cationic intermediate as shown in Scheme 5.17. ... 

Scheme 5.18 Regioselective generation of an N-acyliminium ion pool by oxidative C—Si bond dissociation...

For example, the anodic oxidation of a silyl-substituted carbamate to generate a solution of N-acyliminium ion and the cathodic reduction of cinnamyl chloride in the presence of chlorotrimethylsilane to generate the corresponding allylsilane can be carried out simultaneously in a single electrochemical microflow cell under continuous flow conditions (Figure 5.10). The N-acyliminium ion, the anodic product, is allowed to react with the allylsilane, the cathodic product, to give the coupling product. 

The radical generated by the reduction of an N-acyliminium ion pool can be trapped with an electron-deficient olefin, such as acrylate ester, which is known to be a good radical acceptor (Scheme 5.29). In the presence of a large excess amount of proton, a 1 1 adduct is obtained in good yield. A mechanism involving radical addition to the electron-deficient olefin followed by one-electron reduction to give the carbanion or enolate anion that is trapped by a proton has been suggested. 

Scheme 5.29 Addition of a carbon radical generated from an N-acyliminium ion pool to an electron-deficient olefin...

In Chapter 6 we discussed the remarkable mixing effect of Friedel-Crafts reactions. Let us briefly review it and then discuss its application to various aromatic and heteroaromatic compounds (Scheme 8.7). Friedel-Crafts reaction of 1,3,5-trimethoxybenzene with a highly reactive electrochemically generated N-acyliminium ion pool using a conventional macrobatch reactor results in the formation of an essentially 1 1 mixture of the monoalkylation product and the dialkylation product. The reaction is very fast and is complete within Is even at —78°C. 

The effect of micromixing in the iodination reaction is smaller than that observed for the Friedel-Crafts alkylation using N-acyliminium ions. The smaller effect seems to be ascribed to the smaller rate of iodination, because computational fluid dynamics simulation indicated that the effect of the micromixing on the product selectivity of a competitive consecutive reaction increases with an increase in the reaction rate. Therefore, the electrochemically generated I seems to be less reactive than the N-acyliminium ions. 

For synthetic applications the N-acyliminium species (1) is nearly always generated in situ because of its high reactivity. Heterolysis of an acetal-like structure of type (2) is a very popular method to effect N-acyliminium ion reactions. In most cases X is a hydroxy, alkoxy or acyloxy function and an acidic catalyst is used to generate (1). If X is methanesulfonyloxy, no catalyst is required, as thermal conditions suffice to produce the intermediate. If X is methoxy or ethoxy, precursor (2) is usually a stable molecule, which allows the execution of diverse reactions under neutral or basic conditions elsewhere in the molecule before the (V-acyliminium intermediate is employed. 

In addition to heterolysis of compounds of type (2), N-acyliminium intermediates (1) are also obtained by protonation of Af-acylimines (27) and by protonation of enamides or enecarbamates (28). The former method is mainly of theoretical interest, Ixcause /V-acylimines (27) are rather unstable compounds. The latter technique is occasionally applied, although compounds (28) are usually synthesized through elimination of HX from (2). Other preparatively very useful methods for the in situ generation of the N-acyliminium ion are the acid-mediated coupling of an aldehyde (or ketone) with a primary (or secondary) amide or a nitrile, and the thermal reaction between an acid chloride and an imine. ... 

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